A 44-year-old male with no substantial medical history was injured falling off his road bike at 25 mph and sustained a traumatic brain injury resulting in a marked expressive dysphasia. CT brain demonstrated a small left subdural haematoma, left temporal contusion and right petrous temporal bone fracture. He did not require surgical intervention. Forty eight hours after injury he developed a lower motor neurone facial weakness secondary to the temporal bone fracture, therefore dexamethasone was commenced.

Q Define traumatic brain injury ?

TBI is a non-degenerative, non-congenital insult to the brain from an external mechanical force causing temporary or permanent neurological dysfunction, which may result in impairment of cognitive, physical and psychosocial functions

Q What are the Endocrine problems associated with traumatic brain injury ?

Post traumatic hypopituitarism (PTHP)

Diabetes Insipidus

Hyponatremia (SIADH , Cerebral salt wasting)

Q Which are the risk factors associated with Pituitary dysfunction after traumatic brain injury ?

Diffuse axonal injury

Fracture of skull base

Older age

Q Does the severity of GCS (Glasgow common scale) associated with pituitary dysfunction ?

Q Which inflammatory mediator is related involvement leads to SIADH in TBI ?

IL6 increases release of Vasopressin

It leads to SIADH after TBI

Q Which type of forces damage the Hypothalamic pituitary unit ?

Shearing forces tend to cause damage to midline structure- more likely to be involved in Hypothalamic pituitary damage

Q What type of skull fracture can cause direct pituitary damage ?

Basal skull fractures

Q Which pituitary hormones increase and which reduce after an acute traumatic event ?

ACTH, GH, Prolactin – increase

FSH/LH and TSH- reduce

Q When does diabetes insipidus occur in Acute TBI ?

It generally manifests on day 5-10

It is often transient

Q In what period after brain injury does post traumatic hypopituitarism occur ?

Time period is variable from 1 months to 23 years

In 75% of patients it occurs within the first year

35% cases within first 3 months

Q What type of damage predominantly leads to PTHP ?

Vascular damage

Shearing axonal injuries

Q Which part of the blood system of pituitary is most vulnerable to damage ?

The damage most predominantly occurs in the long hypophyseal portal system that goes through the sellar diaphragm

This part is most vulnerable to mechanical damage

Q Describe the percentage of various hormonal injuries following PTHP ?

GHD – 30%

Gonadotropin deficiency – 28%

ACTH Deficiency – 18%

Thyrotropin deficiency – 18%

Diabetes insipidus- 2.7 %

Hyperprolactinemia- 0-12%

Hypoprolactinemia- also reported

Q When should pituitary evaluation be done after TBI ?

Generally done 3- 6 months after head injury

On Day 5 of admission his sodium level fell.

Q What are the causes of Hyponatremia following Traumatic brain injury ?

SIADH

Cerebral salt wasting

Central Adrenal insufficiency

Q What are the Diagnostic criteria for SIADH ?

Serum osmolality <280 mom/kg

Urine osmolality >100 mom/kg

Urinary sodium >30 meq/l

Euvoluemic patient

Adrenal insufficiency and hypothyroidism ruled out

Low uric acid

No acid base balance

Normal potassium

Q Describe the management of SIADH ?

The management of SIADH deals mainly with management of Hyponatremia.

Before correction of hyponatremia you need to answer following questions :

How Rapidly did the hyponatremia develop ?

How severe is the hyponatremia ?

Is the patient symptomatic ?

In most cases of asymptomatic chronic , mild to moderate hyponatremia, free fluid restriction is mainstay of treatment.

Initially attributed to SIADH, his sodium continued to fall rapidly despite fluid restriction and slow sodium tablets. Baseline paired serum and urine osmolality were 265 and 595 respectively with urine sodium of 191 mmol/L. He was referred to endocrinology who suspected a diagnosis of CSW on the basis of failure of resolution with fluid restriction, low JVP and high urine output.

Due to reduced central sympathetic outflow prevents activation for RAS in state of hypovoluemia loss of Sodium in urine

Q Which is more common SIADH or CSW ?

SIADH is more common

Q When is CSW generally seen after neurosurgical procedure ?

Generally seen 10 days after neurosurgical procedure

Q What are the CF of CSW ?

Hyponatremia à cerebral edema à altered sensorium

Dehydration

Polyuria

Q What are the diagnostic criteria for CSW ?

In patient with CNS disorder

Serum sodium <135

Urine osmolality >100

Urine sodium >40

Reduced serum uric acid

Clinical evidence of hypovolaemia

Q Which is the most important feature to distinguish SIADH and CSW ?

It is the status of circulating volume – which is low in CSW

Q What are the essential points to differentiate Cerebral salt wasting from SIADH ?

CSW: With Infusion of fluids there is improvement in hyponatremia and reduction in urine osmolality

SIADH- Infusion of fluid à no improvement in hyponatremia and urine remains concentratedà this is because ADH is not suppressed

Urine output assessment was challenging to interpret initially due to extreme confusion, and agitation preventing catheterisation but his urine output was in excess of 3 L a day at this point despite a 1.5 L fluid restriction. During this time the patient recalls having excessive thirst and a craving for the salt tablets, which he later found unpalatable.

Despite hypertonic saline (1.8% saline) being commenced, his sodium continued to fall, with increased cerebral oedema and worsening confusion. This combination necessitated admission to intensive care with a sodium nadir of 116 mmol/L. A graph of his serum sodium, urine sodium and daily intravenous sodium is shown in Fig. 1.

Q Why is differentiating CSW and SIADH important from treatment point of view ?

Because treatment is opposite

SIADH – there is need for fluid restriction

CSW- there is need for fluid infusion and not restriction

Doing the opposite in both the condition can worsen each of the condition

Q What type of fluid is generally given in CSW ?

Generally isotonic fluid

This is not the case in SIADH where isotonic fluid will worsen the patient

Q Which Pharmacological agent is used in treatment of Cerebral Salt wasting ?

Fludrocortisone

Infusion of 5% saline (>950 mEq of sodium required in first 24 h in ITU) restored serum sodium to low normal levels within 72 h (sodium 134 mmol/L). During his intensive care admission he also required inotropic support which further highlights the extent of his volume depletion. Following the stabilisation of his sodium levels he was stepped back down to the neurosurgical high dependency unit. However, his urinary sodium remained persistently elevated peaking at 254 mmol/L, (urine osmolality 710 mmol/kg) serum sodium fell to 125 mmol/L despite hypertonic saline and he required substantial volume replacement (equivalent of more than 4 L/day of 1.8% saline). Urine output remained persistently high between 3 and 5 L a day over this time.

Fludrocortisone was therefore introduced at 75 µg bd and ultimately increased to 150 µg bd, which resulted in a substantial (threefold) fall in requirements for hypertonic saline that was still required for another 7 days. His sodium remained stable around 130 mmol/L on fludrocortisone alone and he was discharged home 25 days post injury. Fludrocortisone was continued for the next four months.

The dexamethasone initiated at 48 hours was continued for a 1-week course. As a baseline cortisol taken 24 h post the final dexamethasone was 94 nmol/L, he was maintained on hydrocortisone 10 mg bd which was continued until after discharge. A post discharge short synacthen test was normal and hydrocortisone was then stopped.

It took four months to wean him off the fludrocortisone without the occurrence of rebound hyponatraemia suggestive of on-going, albeit mild, CSW. Intriguingly, the attempt in the week after he developed peripheral oedema on fludrocortisone was successful and he has remained stable off fludrocortisone for three months.

This is the case of a 33-year-old man without significant medical history who was incidentally diagnosed with a right neck cystic mass by computer tomography (CT) after a motor vehicle accident. Patient denied diaphoresis, palpitations, diarrhea, constipation, mood changes, or any other symptoms. Physical exam revealed a right-sided tender neck mass, without any other remarkable findings. He did not have history of neck irradiation, thyroid disease, or family history of thyroid cancer. Thyroid function tests were within normal limits (TSH: 1.5 IU/mL). Excisional biopsy of the neck mass reported metastatic, well-differentiated, thyroid papillary carcinoma within lymph node tissue. Pathologic description consisted of a nodular segment, tannish, rubbery specimen with attached membranous cystic tissue. The pathological specimen (lymph node) was distorted and had a well-defined cystic structure within it. While the cystic structure measured 2 cm × 1.5 cm × 1 cm, the lymph node measured 1.5 cm × 1 cm (Figure 2). Due to previous findings, he underwent total thyroidectomy with right neck dissection in order to rule out occult primary carcinoma of the thyroid. Histopathological findings revealed a normal thyroid gland without evidence of papillary thyroid carcinoma and sixteen right neck lymph nodes without evidence of metastasis. Thyroid pathology was meticulously reviewed, without any evidence of papillary thyroid carcinoma identified.

Q What is your impression of this case ?

It seems there is PTC present in a rare ectopic tissue present in the cervical region since the Eutopic thyroid gland has no evidence of thyroid cancer.

Q So this is a case of Papillary thyroid cancer (PTC) post thyroidectomy. Would you give post operative radioactive iodine in this case ?

All patients with PTC donot require radioactive iodine therapy post operatively. In all such cases a post-operative re-staging is done to classify the patient into Low risk, Intermediate risk and high risk.

Radioactive iodine therapy is indicated in those considered to have high risk according to American thyroid association (ATA) guidelines. The following are considered to be high risk

Gross extrathyroidal extension

Incomplete surgery / gross residual disease

Distant metastasis

Post op Tg suggestive of distant metastasis

It is considered in those with ‘intermediate’ risk and not indicated in those with low risk.

Q In which risk category would you classify this patient ?

It is difficult to classify the patient according to ATA classification since there is presence of PTC in the ectopic thyroid gland but not in the eutopic thyroid gland. Also there is no evidence of lymph node metastasis. Hence it would be difficult to classify this patient and hence consider the patient as having intermediate risk and CONSIDER radioactive iodine therapy for this patient.

Q How will you follow up this patient ?

I would not start the patient on LT4 and follow the patient after 6-8 weeks with TSH. If TSH is >30 , patient sent for Radioactive iodine ablation with 30 mCi.

After surgery, thyroid hormone replacement was started. One month after procedure, thyroglobulin was 133.61 ng/ml (1.15–130.77 ng/ml) and thyroglobulin antibodies were 11.8 uU/ml (negative, less than 45 uU/ml).

Q What is interpretation of these reports ?
We donot know if the Tg is stimulated or unstimulated, however in either case Tg is very high and needs evaluation. This would be classified as ‘Biochemical incomplete response’ or ‘Structural incomplete response’ depending on the presence or absence of any remnant tissue in the neck. So I would order a neck ultrasound from an experienced radiologist as my first line of approach.

In retrospect it suggests that the authors should have considered Radioactive iodine ablation post operatively. However, we have an advantage of hind sight and as described above the post operative staging according to ATA was tricky to begin with.

For residual disease in neck the options are close follow up, surgery and radioactive iodine ablation.

In Gross extensive residual disease surgery is the best option. For minimal residual disease surgery is indicated in cases where size of lateral nodes is >1.5 cm. In this case a repeat surgery for local disease would be a better option.

Presence of considerable local disease it is difficult to judge and ablate distant metastasis. Hence ideally surgery would have been a better approach followed by Radioactive iodine ablation if needed. In the currently scenario there seems to be a false reassurance of absence of distant mets on a radioactive iodine pre-therapy scan. I would advice the authors for a close post operative follow up of this case.

Learning objective.

This is a rare case where PTC in an ectopic thyroid tissue that too in lateral neck region without evidence of malignancy in the eutopic thyroid.

In cases where post-operative ATA staging is ambiguous, it is better to consider a higher stage than a lower stage.

A girl of 11 years and 3 months was referred to our unit due to enlargement of the clitoris associated with obstructive symptoms at micturition. According to her prenatal history, amniocentesis was conducted due to advanced maternal age, revealing a 46, XY karyotype. Pregnancy was otherwise uncomplicated. Cesarean section was performed at the gestational age of 40 weeks and 3 days due to cephalopelvic disproportion and failure to progress. The newborn was a healthy full-term baby, without electrolyte imbalance, presenting with an inadvertent female phenotype. In order to assess the discordance between chromosomal and phenotypical gender, the SRY gene was examined and found to be present, while imaging of the brain, hypothalamus, and pituitary gland was normal. At that time-point, the family decided to take no further action.

Q What are cause of 46 XY with unambiguous female genitalia at birth ?

Complete androgen insensitivity syndrome (CAIS)

Complete gonadal dysgenesis (CGD)

17 alpha hydroxylase deficiency

Q How will you distinguish CAIS from Complete gonadal dysgenesis ?

CAIS will have absent Mullerian structures while Complete gonadal dysgenesis may have Mullerian structures present.

Gonads are not palpable in complete gonadal dysgenesis while they may be present in the inguinal region or labioscrotal region in CAIS

On measuring the Serum testosterone- CAIS will have testosterone in normal male range while CGD will have low testosterone.

Anthropometric characteristics at presentation were in the normal range for girls at the patient’s age, while physical examination revealed excessive clitoriomegaly resembling a phallus of 6 cm and a shallow vaginal orifice.

Q Would you plot the patient’s growth with a female growth chart or in the male growth chart ?

You will plot it in female growth chart only, however it is an area of debate.

However most studies done have plotted it on female growth chart

While physical examination revealed excessive clitoridomegaly resembling a phallus of 6 cm and a shallow vaginal orifice. No testes were palpable.

Q What do you think of the diagnosis now ?

It seems odd that the child had normal female genitalia at birth and now has significant clitoromegaly and ambiguous genitalia.

It is more likely the ambiguous genitalia was missed at birth which seems strange because they already knew that the child was 46 XY on amniocentesis !

Q The breast they say is Tanner stage I , what will you narrow down your DD do ?

With absent breast enlargement ,5 alpha reductase 2 appears to be a more appopriate diagnosis

However it is possible that the child has not reached puberty , hence it would be premature to judge

Imaging of the lower abdomen with ultrasound and MRI revealed bilateral testicular tissue at the intraperitoneal space near the inner inguinal ring, hypoplastic penile cavernous bodies within a sizable clitoris, and the presence of a rudimentary prostate along with seminal vesicles.

Q Are wolffian duct derivatives present in CAIS ?

No generally not

Even if they are present they are rudimentry

Q There are absent Mullerian structures, which differential seems less likely with this ?

The presence of testis and absent of Mullerian derivatives make the diagnosis of partial gonadal dysgenesis less likely.

The ratio of T to -androstenedione (Δ4A) was >0.8, excluding 17β-hydroxysteroid dehydrogenase-3 (17β-HSD-3) deficiency, while the ratio of T to dihydrotestosterone (DHT) was <20, excluding 5α-reductase deficiency. The high elevation of T concentration (ΔΤ) after the hCG stimulation (>100 ng/dl) indicated the presence of testicular tissue, excluded gonadal dysgenesis, and supported the diagnosis of AIS (Table 2). Imaging control revealed the presence of bilateral testicular tissue. The combination of almost female phenotype with minimal virilization and proper male gonadal function was supportive for the diagnosis of severe PAIS

Q Give a typical protocol for HCG stimulation test ?

There are various protocol for HCG stimulation test. We will discuss one protocol which we follow

Baseline Testosterone, DHT and Androstenedione are sent

HCG is given as a single dose of 5000 IU for an older child IM

The sample are repeated after 72 hours

Q What ratios suggest 5 alpha reductase 2 and 17 beta HSD 3 ?

Stimulated T:DHT ratio > 27:1 – suggest 5 alpha reductase 2 defect

T: A ratio <0.8 suggests 17 beta HSD 3 deficiency

Q What small care you must take while calculating the ratios of T:A in this case?

The values of androstenedione are in ng/ml. Hence when we calculate the ratio, we need to convert it to ng/dl

Q What would you do for further management of this case ?

This is a case of PAIS raised as a female.

Since the child is already raised as female it would be wise to continue the same gender assignment.

I would consider going a gonadectomy and replacing the child with estrogen replacement.

I would also consider doing appropriate genital reconstruction.

Q What is the risk of gonadoblastoma in this case ?

PAIS with non scortal gonad have high risk of gonadoblastoma.

Reasonably, the assignment of female gender was recommended, since the patient had already been raised as a girl and the relevant interventions would be minimal. In addition, the testes that were found during imaging studies had to be removed, as they were atrophic and of increased risk for malignant change. Interestingly, the parents suggested that the child itself should be fully informed and participate in the final decision, and therefore, from the very first beginning, the patient was involved in all discussions made with the attending physicians. It is noteworthy that, being aware of the condition, she stated: “It does not matter if I am female or male, most of all I am a human being and thus gender assignment will not play any significant role in my future life.” Eventually, female gender was preferred by both the patient and the parents, and gonadectomy as well as cosmetic surgery of the external genitalia were successfully performed.

Learning points

Be careful while calculating the T:A and T:DHT ratios. The units of the numerator and denominator should be the same.

PAIS with non scrotal gonad have a high risk of gonadoblastoma and gonadectomy must be done , generally before puberty.

Female sex assignment is not inappropriate for PAIS, especially if the child is raised as a female.

Editorial note: In this case we have questioned the diagnosis the authors have made. The idea of this is not to criticize the efforts of the authors, but to point out an obvious flaw or error made in the diagnosis in this case. If you disagree with our explanation please feel free to send me an email on endocrinecases@gmail.com

A 11 years old girl of a consanguineous parents belonging to a low socioeconomic status, hailing from Nazirabazar, Dhaka, was admitted at Dhaka Medical College Hospital on 07/03/07 with inward bending of both legs for last 4 years, not gaining height in comparison to other children of same age and dental caries for 2-3 years.

She had no history of polyuria, dysuria, jaundice, recurrent chest infections or recurrent attacks of diarrhoea and not on long term anticonvulsant drugs.

Q What is the importance of Polyuria in case of Rickets ?

Polyuria with rickets is suggestive of Renal tubular acidosis, Barrter’s syndrome and certain cases of CKD.

Birth history was uneventful and was partially immunized as per EPI schedule. After birth she was predominantly breast fed for only 5 successive months and currently she is on family diet, i.e., rice, vegetable, fruits but low quantity of fish, meat, milk and egg as they are unable to afford those.

Q Are any of these good sources of vitamin D ?

Since this case is from Bangladesh, food fortification status of general foods is not known.

However, fatty fishes are good source of vitamin D , so the child may be receiving some vitamin D

Though her milestones of development were normal, her linear growth and also weight were not satisfactory as compared to that of other children of her age. Exposure to sunlight was adequate as she used to play along with other children in open air. Her father did not have the same disease and died of kidney disease two years back. Her mother and sibs are healthy

On examination, her pulse was 40/min, BP-100/60 mm Hg and temperature was normal.

The TRP was 68% (N: 78-98%) which confirmed loss of excess phosphate through urine. However, serum 1-α-hydroxylase level could not be done. All parameters of electrolytes were normal. Benedict’s test showed no glucosuria.

Both the clinical features and laboratory parameters were consistent with familial hypophosphatemic rickets.

Q Do you agree with the diagnosis ?

No

Infact in my opinion the diagnosis in this case is most likely nutritional rickets due to vitamin D deficiency

Q What is the most important investigation that has been missed out in this analysis ?

A 25-hydroxy- vitamin D level is not done.

Q What are the points in favour of this being a nutritional rickets ?

Osteopenia in X-ray is a features of nutritional rickets and it is NOT seen in XLRH

The increase TRP can be very well explained by the secondary hyperparathyroidism.

Q You say it is secondary hyperparathyroidism , but the PTH levels is normal !

PTH assay depends much on the transport.

Improper transport of sample in cold chain can lead to reduction in PTH values and hence false low PTH.

This is a well known fact and activation of thrombin is responsible for lowering of PTH values in the sample.

Hence I believe that the PTH levels were false low.

Both the clinical features and laboratory parameters were consistent with familial hypophosphatemic rickets. So, she was treated with Joulie solution, an oral phosphate suspension made up of sodium phosphate (136 gm/L) and phosphoric acid (58.8 gm/L)5 1.5 tsf every 4 hourly. Active form of vitamine D (1-25 dihydroxy cholecalciferol) was also given in the form of Dicatrol capsule (0.25mcg) 6 hourly.

Along with treatment we consulted with orthopaedic department. She was advised to continue the treatment and for regular follow up. After 2 weeks of treatment with oral phosphate and dicatrol, significant radiological improvement was documented. Genetic counseling was also done. As the disease is X-linked, the defective gene may come either from father or from mother. Unfortunately, the genetic study is not possible in Bangladesh. As the father died two years back, there is no chance to have any more children.

Q So if the diagnosis was probably incorrect, why did the child respond to treatment ?

The child was given active vitamin D supplementation.

If the child truly has vitamin D deficiency as we are thinking, she would have responded to active vitamin D supplementation as well.

Learning objective

When dealing with a case of rickets, it is always important to rule out common things first. Vitamin d deficiency (nutritional rickets) is far more common compared to other forms of rickets and must always be ruled out before further investigations are considered.

Vitamin D deficiency with secondary hyperparathyroidism ALSO causes loss of urine phosphate and hence TRP will be reduced in such cases.

TRAbs and TPOAbs were negative and thyroid ultrasound scan showed no evidence of thyroid disease. TRAb measurement was performed using a commercial third-generation ELISA kit that detects both thyroid-stimulating (TSAbs) and -blocking antibodies (TBAbs) with manufacturer specificity and sensitivity of 100 and 95%, respectively, and positive cut-off of >0.4 U/L (RSR Laboratories, Cardiff, UK)

In the ELISA, serum TRAbs inhibit the binding of human biotin-labeled monoclonal antibody to immobilized recombinant TSH receptor on the ELISA plate. The amount of M22-biotin bound to the plate is then determined by the addition of streptavidin peroxidase and tetramethylbenzidine and the absorbance of the mixture is read at 450 nm using a plate reader

Q What is the role of measurement of TSH receptor antibody ?

TSH receptor antibody would help in confirming the diagnosis of Graves’ disease and hence TAO

It will also help in assessing the severity of the disease, guide management decision and help in follow up of the patient

Q How do TRAb antibodies predict the outcome of the patient with TAO ?

Higher TRAb levels at the time of diagnosis are associated with worse clinical course and poor outcomes.

Q What are the subtypes of TSH receptor antibodies ?

Stimulating – TSI à Graves’ disease

Blocking – TBI or TBII – Atropic thyroiditis

Neutral

Q What are the methods by which TSH receptor antibodies are tested ?

There are two major ways in which TSH Receptor antibodies are tested

The first is TBII assay (Receptor method) and the other is functional biological assay for TRAb.

TBII assay cannot differentiate between stimulating and blocking antibodies while the functional assay can differentiate between the two.

Q Tell me something about TBII assay ?

TBII assay are based on the principle of TSH binding to the TSH receptor and the antibodies competing with this binding.

The biological assay are based on the principle of cAMP generation on binding of ligand with TSH

TSI activates TSH receptor leading to generation of cAMP and TBI reduces the generation of cAMP

Current assays are based on Mc4-CHO cell lines

However interpretation of the results is sometimes difficult since the same patient may have blocking as well as stimulating antibodies.

Hence these are mainly used in research setting.

Q What kind of assay is used in this case ?

It is a TBII assay which is used

It would not distinguish between TSI and TBI

Q What is your interpretation of the CT scan in this patient ?

The CT scan clearly shows inferior rectus thickening on both the sides.

Hence eventhough clinically the patient has mainly right sided proptosis, based on CT scan both the sides are involved.

Thickening of the EOM with sparing of the tendon insertion site is characteristic of TAO.

However, in this cases sparing of the tendon is not demonstrated as alternate cuts showing inferior rectus insertion are not provided.

A CT scan of the orbit showed bilateral asymmetrical enlargement of the inferior rectus, more marked on the right than on the left, and was highly suggestive of GO inflammation (Fig. 1). An MRI orbit (Fig. 2) also confirmed inflammation in keeping with GO (Fig. 2). There was no evidence of structural or other inflammatory lesions on imaging. Serum calcium and angiotensin-converting enzyme (ACE) levels were normal.

Q So what is your diagnosis at end of the investigations ?

Since now there is CT evidence of bilateral involvement of the EOM, the diagnosis would most likely still be TAO.

Again absence of any other tumor or pathology would also favor the diagnosis of TAO, albeit euthyroid TAO.

Q Since there is still no confirmed diagnosis of TAO, what would you consider doing next ?

Though this seems nothing else other than TAO based on clinical judgement, the patient being euthyroid and absence of significant elevation of TRAb antibody does create doubts about the diagnosis.

In option in such a case would be to perform FNAC or biopsy in such a scenario.

Q What is the role of Functional imaging modalities in such cases of proptosis where diagnostic confusion exists ?

In a study done by García-Rojas et al , FDG- PET is useful for distinguishing EOM in TAO versus other conditions.

In their study they found that patients with TAO has higher SUVmax uptake of FDG in EOM compared to those having non thyroidal cause of EOM involvement.

Q Assuming it is TAO, Based on the evidence provided, what is the Clinical activity score in this patient ?

The CAS would be 3 based on the evidence provided which would make it active ophthalmopathy.

According to the authors, the MRI is also suggestive of active inflammation.

Q Describe the EUGOGO clinical activity score ?

EUGOGO Clinical activity score

Q What is the severity of the TAO based on the evidence provided ?

Based on the ATA grading it would be Grade IV since there is involvement of EOM (NO SPECS classification)

It would be difficult to classify the patient based on the EUGOGO assessment of severity since the measurement of proptosis and severity of the soft tissue involvement is not provided.

She was treated symptomatically in the regional multidisciplinary Thyroid Eye Disease clinic with topical lubricants and fitted with a corrective prism. She later underwent a surgical recession of 4mm of the inferior rectus muscle with complete resolution of diplopia and headaches. A biopsy of the inferior rectus muscle taken at surgery showed a low-grade infiltrate with B and T lymphocytes. She had no further eye complaints and continued to be followed up with annual thyroid function tests.

Twenty-four months after initial presentation, she developed symptoms of anxiety, sweating, tremor, and palpitations. She had no goiter or eye signs. Her thyroid hormone levels were consistent with T3 toxicosis: TSH 0.04U/L, FT3 9.56mol/L, and FT4 15.5pmol/L. At this point, repeat TRAb and TPOAb measurements were positive: 7.6IU/L and 67.9IU/mL, respectively (Table 1). She was commenced on carbimazole initially and subsequently treated with a ‘block and replace’ regimen of carbimazole and levothyroxine. She responded satisfactorily with clinical and biochemical resolution and treatment was discontinued after 12 months. Her vision has since remained intact with no further disturbance of thyroid function.

Q Describe the timing of diagnosis of TAO in relation with Graves’ hyperthyroidism ?

Timing with Graves’ hyperthyroidism

20% – Precedes hyperthyroidism

40%- diagnosed concurrently

20%- Follows the diagnosis of hyperthyroidism

20%- Occurs after Radio-active iodine therapy

Q What percentage of people with TAO have hyperthyroidism, euthyroidism and hypothyroidism ?

With patients having TAO

80%- Hyperthyroid

10-20%- Euthyroid

1-10%- Hypothyroid

Q What are the features of Euthyroid TAO compared to hyperthyroid TAO ?

Euthyroid TAO compared to hyperthyroid TAO are:

Milder

Less severe EOM

Unilateral more often

Lesser soft tissue involvement

Absence of lid lag and Upper eyelid retraction.

Lower degree of TRAb antibody

Q What is the explanation of the absence of TRAb antibody in this case ?

Absence of TRAb antibody may be due to low titres of this antibody in case of Euthyroid graves orbitopathy.

The tests use for TRAb antibody donot have 100% sensitivity.

Antibodies against IGF-1 receptor have also been implicated in pathogenesis of TAO.

Learning points

TRAb antibodies are an important test for diagnosis of TAO especially in cases of Euthyroid TAO or in cases where diagnostic confusion exists. However, in some cases of TAO, TRAb antibodies may be negative or in low titres to be detected at the time of early presentation.

CT scan of the orbits is an important diagnostic tool in case of proptosis where diagnosis of TAO is not certain.

FNAC, Biopsy, Surgical resection and FDG PET are other modalities used for differential diagnosis of proptosis.

Onset of TAO may preceed the onset of hyperthyrodisim in patient with Graves’ disease in about 10-20% cases.

A 1.4-year-old boy was admitted with complaints of pubic hair development, penile enlargement, linear growth acceleration, acne and increased aggressive behavior. His mother had become aware of enlargement of the genitals by 6 months of age

Q What is definition of precocious puberty ?

Age of onset of puberty 2 -2.5 SD earlier than normal

Ie Onset of puberty before 8 years on girls and before 9 year in boys

Q Classify the various causes of precocious puberty (PP)in boys based on age of onset ?

Onset in infancy

Hypothalamic hamartoma

Adrenal tumor

Onset in early childhood

Hypothalamic hamartoma

Familial male limited precocious puberty (FMPP)

Onset in late childhood

CNS tumors

CAH

Idiopathic

He had healthy parents non-consanguineously married and there was no family history of precocious puberty.

At physical examination, his height was 96 cm (+5.38 standart deviation score (SDS)) and weight was 17 kg (+2.0 SDS). He had an extremely muscular body build, a deepened voice and acne. Penile stretch length was 13 cm (>2 SDS); the left testicular volume was 3 mL and the right was 4 mL. Pubic hair was appropriate for Tanner stage 3 (Figure 1a). He did not have any café au lait spots.

Q Can you deduce from this clinical presentation whether the patient has GDPP or GIPP (gonadotropin dependent or independent precocious puberty)

From this history and examination it seems the child most likely has GIPP.

Peripheral precocious puberty findings with a testicular volume of 4 mL suggested a tumor secreting beta-human chorionic gonadotropin (hCG) or a testicular tumor secreting testosterone; an activating mutation in the LH receptor and McCune Albright syndrome were also considered.

Abdominal magnetic resonance imaging (MRI) revealed normal findings.

A low serum beta-hCG (presence of a beta-hCG-secreting tumor.

He did not have any abnormality in bone scintigraphy screening.

A testicular ultrasonography showed a solid mass of a size of 2×2 mm in the right testicle. A surgical intervention was performed. During the operation, the testis was mobilized by inguinal incision and a 2×2 mass was detected. In cold ischemia conditions, the mass was excised by testis-saving procedure and sent for histopathological evaluation.

Q What is the treatment of GIPP in boys ?

For Tumor of Testis, adrenal or GCT: Surgery and/or other modes of therapy for the tumor

CAH- glucocorticoids

For other causes- anti-androgen therapy

Q What is bicalutamide ?

It is a pure androgen receptor antagonist

In GIPP – it is given in dose of 2 mg/kg

Q What is done if GIPP patients develop secondary CPP ?

GnRH agonist is given additionally

Q What is the treatment of Familial male limited precocious puberty (FMPP) or testitoxicosis ?

Anti-androgen treatment with bicalutamide (50 mg/day) and aromatase inhibition with anastrozole (1 mg/day) were initiated. A normal testosterone level could not be obtained and another surgery was planned. The same inguinal incision was performed and vascular pedicle was secured in cold ischemia conditions. The mass was not localized by visual examination. Intraoperative ultrasonography demonstrated a 3×3 mm mass and with the guidance of the probe, the mass was found and excised by another testis-saving procedure. Histopathological examination revealed the diagnosis of nodular Leydig cell hyperlasia again.

Q What are the typical histological findings of the testis seen in case of FMPP ?

Leydig cell hyperplasia is typical

Hyperplasia of Sertoli cell and spermatogenesis is also present because of increase intratesticular testosterone concentration.

Since the patient met the criteria for the diagnosis of testotoxicosis, a genetic analysis for LHCGR gene was performed.

Sequence analysis of all coding regions and exon-intron boundaries were done by in house designed primers using Sanger sequencing technique and a novel mutation c.830G>T (p.S277I) (heterozygous) was described (Figure 1b). In silico evaluation tools including Mutation taster, SIFT and Polyphen 2 predict this variant as a disease-causing mutation. Parental analysis was normal, then this variation was most probably a de novo pathogenic variant. Screening of 200 healthy people for this variant was done and no one had this mutation.

Q What is the typical age of presentation of FMPP ?

They typically present between 1-3 years of age.

However in this case the onset was even before 1 year of age.

This may be because of the novel mutation found.

Such cases with earlier onset of FMPP have been reported in literature.

Q What is the mode of inheritance of Familial male limited precocious puberty (FMPP) ?

FMPP has an autosomal dominant inheritence with more than 90% penetrance.

Cyproterone acetate was added to the treatment regimen because the suppression of pubertal progression and serum testosterone levels was not sufficient, but it was withdrawn in one month because of increases in liver enzymes which could not be associated with another cause; liver enzymes became normal after the cessation of the drug.

In the 20th month of treatment, GnRH stimulation revealed a pubertal response and a GnRH analogue was added to treatment.

Q Why do children who have GIPP also develop Central precocious puberty secondarily ?

Excess sex steroid exposure as in McCune albirght or CAH can lead to secondary CPP

Two theories

Priming effect of sex steroids

On reducing Sex steroid with treatment – there is loss of negative feedback à rebound activation of gonadotropin axis

In his follow-up at age 3.8 years, despite bicalutamide (100 mg/day), anastrozole (2 mg/day) and GnRH analogue treatments, sufficient suppression of puberty and decline in serum testosterone levels were not achieved (Table 2). Antiandrogen treatment with bicalutamide (androgen receptor antagonist) was changed to ketoconazole (androgen synthesis inhibitor) in a dose of 10 mg/kg/day. A treatment regimen of ketoconazole, anastrozole and a GnRH analogue led to a decline in serum testosterone level from 900 ng/dL to 490 ng/dL on the 3rd day of the treatment. At the 3rd month of ketoconazole (15 mg/kg/d) treatment, serum testosterone level decreased to 125 ng/dL without any sign of side effects; whether this benefit will be sustained or not needs to be evaluated in the long term.

Learning points

Familial male limited precocious puberty (Testitoxicosis) is an important cause of Gonadotropin independent precocious puberty (GIPP) in boys and generally present between ages 1-3 years but may present earlier.

Absence of testicular enlargement in presence of other features of Precocious puberty points towards GIPP, however FMPP may have mild testicular enlargement because of Leydig cell hyperplasia and/or hyperplasia of seminifeous tubules and sertoli cells due to intratesticular testosterone.

Q What is done is incidental testicular lesion is found in scrotal ultrasound ?

Go for tumor marker

If negative- ultrasound follow up is adequate

Q Which are the tumor markers for testicular Germ cell Tumors ?

AFP

LDH

Beta HCG

Q What is the relation between type of cancer and the tumor markers ?

Non Seminomas- beta HCG and/or AFP is elevated in 80% of cases

Seminomas- beta HCG is elevated in 20% cases, AFP is not elevated

Q Are tumor makers alone sensitive to diagnose GCT ?

No

They are not sensitive enough to make a diagnosis without histological confirmation

Q Which is the gold standard for diagnosis of testicular GCT ?

Radical inguinal orchiectomy is the gold standard for diagnosis of testicular GCT

It gives histopathological confirmation

Neither ultrasound nor tumor markers can replace it

Q What is the next step for this child ?

The child has tumor marker for GCT which are negative.

However, since the child has gynecomastia and advanced bone age with this testicular mass, evaluation is required.

I would consider doing an orchidectomy of the involved testis.

The committee on tumoral diseases agreed on the decision to perform a testis-sparing surgery in the light of examination of frozen sections. However the large and cystic mass left no adequate testis tissue to conserve, so a left orchiectomy was performed.

Abdomen and thorax Computed Tomography (CT) imaging were normal. Histopathological investigation revealed a sertoli cell tumor which had positive staining with inhibin, vimentin, and calretinin. Gynecomastia regressed at the end of three months following the operation.

Q Sertoli cell tumors are associated with which conditions ?

Carney’s complex

Peutz Jeghers syndrome

Q What is the characteristic of these tumor in Carney’s complex ?

They are large cell calcifying Sertoli cell tumors

They generally appear in the 2nd decade

They are generally non hormonal producing

Q What is the feature of the tumor in Petz Jeghers ?

They have high aromatase activity and hence they often produce gynecomastia

Q What about Sertoli cell tumors which are not a part of the above disorders, are they hormonally active ?

No, They are not

Q Which is the most common testicular tumor in infants ?

Juvenile granulosa cell tumor is the most common testicular tumor in infants

It occurs in first few months of life

They generally have good prognosis

They rarely present with ambigious genitalia

Q What about adult granulosa cell tumors ?

They are more likely to be hormonally active

They present in middle age with gynecomastia and feminizing features

Q Which important immunohistochemical is common in the various sex cord tumors ?

Sertoli cell tumors have high aromatase activity and hence can present with gynecomastia. However, most sertoli cell tumors occur in context of PJS or Carney’s complex and are often bilateral. Unilateral Sertoli cell tumor presenting with gynecomastia in prepubertal child without evidence of any syndrome is rare.